Medicaments for the treatment of chronic obstructive pulmonary disease

ABSTRACT

A pharmaceutical composition comprising a compound of formula 1  
                 
wherein: n is 1 or 2; 
     R 1  is hydrogen, C 1 -C 4 -alkyl, halogen, OH, or —O—C 1 -C 4 -alkyl;    R 2  is hydrogen, C 1 -C 4 -alkyl, halogen, OH, or —O—C 1 -C 4 -alkyl;    R 3  is hydrogen, C 1 -C 4 -alkyl, OH, halogen, —O—C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof; and a pharmaceutically acceptable excipient or carrier, and methods for using the pharmaceutical formulation in the treatment of chronic obstructive pulmonary disease (COPD).

RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.10/705,012, which claims priority to U.S. Ser. No. 60/434,038, filedDec. 17, 2002, and German Application No. 102 53 282.6 filed Nov. 15,2003, each of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the use of the compounds of generalformula 1

wherein the groups R¹, R², and R³ may have the meanings given in theclaims and in the specification, for preparing a pharmaceuticalcomposition for the treatment of chronic obstructive pulmonary disease(COPD), as well as new compounds of general formula 1 and processes forpreparing them.

BACKGROUND OF THE INVENTION

Betamimetics (β-adrenergic substances) are known from the prior art.Reference may be made, for example, to the disclosures of U.S. Pat. No.4,460,581, which is hereby incorporated by reference, which proposesbetamimetics for the treatment of a variety of complaints.

For drug treatment of diseases it is often desirable to preparemedicaments with a longer duration of activity. As a rule, this ensuresthat the concentration of the active substance in the body needed toachieve the therapeutic effect is guaranteed for a longer period withoutthe need to re-administer the drug at frequent intervals. Moreover,giving an active substance at longer time intervals contributes to thewell-being of the patient to a high degree.

It is particularly desirable to prepare a pharmaceutical compositionwhich can be used therapeutically by administration once a day (singledose). The use of a drug once a day has the advantage that the patientcan become accustomed relatively quickly to taking the drug regularly atcertain times of the day.

The aim of the present invention is therefore to provide betamimeticswhich have a therapeutic benefit in the treatment of COPD and arecharacterized by a longer duration of activity and can thus be used toprepare pharmaceutical compositions with a longer duration of activity.A particular aim of the invention is to prepare betamimetics which, byvirtue of their long-lasting effect, can be used to prepare a drug foradministration once a day for treating COPD. In addition to the aboveobjectives, the present invention also sets out to provide betamimeticswhich are not only exceptionally potent but are also characterized by ahigh degree of selectivity with respect to the β₂-adreno-receptor.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that the abovementioned problems aresolved by compounds of general formula 1.

Accordingly, the present invention relates to compounds of generalformula 1

wherein:

-   n denotes 1 or 2,-   R¹ denotes hydrogen, C₁-C₄-alkyl, halogen, OH, or —O—C₁-C₄-alkyl;-   R² denotes hydrogen, C₁-C₄-alkyl, halogen, OH, or —O—C₁-C₄-alkyl;    and-   R³ denotes hydrogen, C₁-C₄-alkyl, OH, halogen, —O—C₁-C₄-alkyl,    —O—C₁-C₄-alkylene-COOH, or —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl,-   for preparing a pharmaceutical composition for the treatment of    COPD.

It is preferable to use compounds of general formula 1, wherein:

-   n denotes 1 or 2;-   R¹ denotes hydrogen, halogen or C₁-C₄-alkyl;-   R² denotes hydrogen, halogen or C₁-C₄-alkyl; and-   R³ denotes hydrogen, C₁-C₄-alkyl, OH, halogen, —O—C₁-C₄-alkyl,    —O—C₁-C₄-alkylene-COOH, or —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl,-   for preparing a pharmaceutical composition for the treatment of    COPD.

It is preferable to use compounds of general formula 1 wherein:

-   n denotes 1 or 2;-   R¹ denotes hydrogen, fluorine, chlorine or methyl;-   R² denotes hydrogen, fluorine, chlorine or methyl; and-   R³ denotes hydrogen, C₁-C₄-alkyl, OH, fluorine, chlorine, bromine,    —O—C₁-C₄-alkyl, —O—C₁-C₄-alkylene-COOH, or    —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl,-   for preparing a pharmaceutical composition for the treatment of    COPD.

It is particularly preferred to use compounds of general formula 1wherein:

-   n denotes 1 or 2;-   R¹ denotes hydrogen, methyl or ethyl;-   R² denotes hydrogen, methyl or ethyl; and-   R³ denotes hydrogen, methyl, ethyl, OH, methoxy, ethoxy,    —O—CH₂—COOH, —O—CH₂—CO—O-methyl, or —O—CH₂—COOethyl,-   for preparing a pharmaceutical composition for the treatment of    COPD.

It is particularly preferred to use compounds of general formula 1wherein:

-   n denotes 1 or 2;-   R¹ denotes hydrogen or methyl;-   R² denotes hydrogen or methyl; and-   R³ denotes hydrogen, methyl, OH, methoxy, —O—CH₂—COOH, or    —O—CH₂—COOethyl,-   for preparing a pharmaceutical composition for the treatment of    COPD.

Also of particular importance according to the invention is the use ofcompounds of general formula 1 wherein:

-   n denotes 1 or 2;-   R¹ denotes hydrogen or methyl;-   R² denotes hydrogen or methyl; and-   R³ denotes hydrogen, OH, methoxy, or —O—CH₂—COOH,-   for preparing a pharmaceutical composition for the treatment of    COPD.

A preferred aspect of the present invention further relates to the useof compounds of general formula 1 wherein n is 1 and the groups R¹, R²,and R³ may have the abovementioned meanings, for preparing apharmaceutical composition for the treatment of COPD.

Another preferred aspect of the present invention relates to the use ofcompounds of general formula 1 wherein n is 1 or 2, R³ denotes a groupselected from among hydrogen, OH, —O—C₁-C₄-alkyl, and—O—C₁-C₄-alkylene-COOH, and wherein the groups R¹ and R² may have theabovementioned meanings, for preparing a pharmaceutical composition forthe treatment of COPD.

Another preferred aspect of the present invention relates to the use ofcompounds of general formula 1 wherein n is 2, R¹ and R² are eachhydrogen, and the group R³ may have the abovementioned meanings, forpreparing a pharmaceutical composition for the treatment of COPD.

In the compounds of formula 1 the groups R¹ and R², if they do notrepresent hydrogen, may each be arranged in the ortho or meta positionrelative to the bond to the benzylic “—CH₂” group. If neither of thegroups R¹ and R² denotes hydrogen, it is preferable according to theinvention to use those compounds of formula 1 wherein the two groups R¹and R² are either in the ortho configuration or both groups R¹ and R²are in the meta configuration, while the use of those compounds whereinboth groups R¹ and R² are in the ortho configuration is particularlyimportant.

In the compounds of formula 1 wherein one of the groups R¹ and R² doesnot denote hydrogen, it may be in the ortho or meta configuration withrespect to the bond to the benzylic “—CH₂” group. In this case it isparticularly preferred according to the invention to use those compoundsof formula 1 wherein the group R¹ or R², which does not denote hydrogen,is in the ortho configuration.

In another aspect, the present invention relates to the abovementioneduse of the compounds of formula 1 in the form of the individual opticalisomers, mixtures of the individual enantiomers, or racemates. It isparticularly preferable to use the compounds of formula 1 as mentionedabove in the form of the enantiomerically pure compounds, while the useof the R enantiomers of the compounds of formula 1 is of particularimportance according to the invention.

In another aspect, the present invention relates to the abovementioneduse of the compounds of formula 1 in the form of the acid addition saltswith pharmacologically acceptable acids as well as optionally in theform of the solvates and/or hydrates thereof.

The present invention further relates to the use of the abovementionedcompounds of general formula 1 for preparing a pharmaceuticalcomposition for once-a-day treatment of COPD.

Moreover, the present invention relates to a process for the treatmentof COPD, characterized in that one or more of the abovementionedcompounds of general formula 1 are administered in therapeuticallyeffective amounts. The present invention also relates to processes fortreating COPD, characterized in that one or more of the above-mentionedcompounds of general formula 1 are administered once a day intherapeutically effective amounts.

The compounds of general formula 1 are partly known from the prior art.Reference is made here to the disclosure of U.S. Pat. No. 4,460,581. Insome cases, however, the compounds of general formula 1 have not yetbeen disclosed in the prior art. Another aspect of the present inventionrelates to these new compounds of formula 1 as such.

Accordingly, the present invention also relates to compounds of generalformula 1

wherein:

-   n denotes 1;-   R¹ denotes hydrogen, halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl;-   R² denotes hydrogen, halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl; and-   R³ denotes C₁-C₄-alkyl, OH, halogen, —O—C₁-C₄-alkyl,    —O—C₁-C₄-alkylene-COOH, or —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl,-   with the proviso that, if R¹ and R² each represent ortho-methyl, R³    cannot simultaneously be OH.

Preferred compounds of general formula 1 are those wherein:

-   n denotes 1;-   R¹ denotes hydrogen, fluorine, chlorine, methyl, or methoxy;-   R² denotes hydrogen, fluorine, chlorine, methyl, or methoxy; and-   R³ denotes C₁-C₄-alkyl, OH, fluorine, chlorine, bromine,    —O—C₁-C₄-alkyl, —O—C₁-C₄-alkylene-COOH, or    —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl,-   with the proviso that, if R¹ and R² each represent ortho-methyl, R³    cannot simultaneously be OH.

Preferred compounds of general formula 1 are those wherein:

-   n denotes 1;-   R¹ denotes hydrogen or C₁-C₄-alkyl;-   R² denotes hydrogen or C₁-C₄-alkyl; and-   R³ denotes C₁-C₄-alkyl, OH, —O—C₁-C₄-alkyl, —O—C₁-C₄-alkylene-COOH,    or —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl,-   with the proviso that, if R¹ and R² each represent ortho-methyl, R³    cannot simultaneously be OH.

Preferred compounds of general formula 1 are those wherein:

-   n denotes 1;-   R¹ denotes hydrogen, methyl or ethyl;-   R² denotes hydrogen, methyl or ethyl; and-   R³ denotes methyl, ethyl, OH, methoxy, ethoxy, —O—CH₂—COOH,    —O—CH₂—COOmethyl, or —O—CH₂—COOethyl,-   with the proviso that, if R¹ and R² each represent ortho-methyl, R³    cannot simultaneously be OH.

Also preferred are the compounds of general formula 1 wherein:

-   n denotes 1;-   R¹ denotes hydrogen or methyl;-   R² denotes hydrogen or methyl; and-   R³ denotes methyl, OH, methoxy, —O—CH₂—COOH, or —O—CH₂—COOethyl,-   with the proviso that if R¹ and R² each represent ortho-methyl, R³    cannot simultaneously be OH.

Also preferred according to the invention are compounds of generalformula 1 wherein R³ denotes methoxy, ethoxy, —O—CH₂—COOH,—O—CH₂—COOmethyl, or —O—CH₂—COOethyl, and R¹, R², and n may have theabove meanings.

The present invention also relates to compounds of general formula 1wherein:

-   n denotes 1;-   R¹ denotes halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl;-   R² denotes halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl; and-   R³ denotes halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl.

The present invention also relates to compounds of general formula 1wherein:

-   n denotes 1;-   R¹ denotes fluorine, chlorine, methyl, or methoxy;-   R² denotes fluorine, chlorine, methyl, or methoxy; and-   R³ denotes fluorine, chlorine, methyl, or methoxy.

In another preferred aspect the present invention relates to thecompounds of general formula 1 wherein:

-   n denotes 1;-   R¹ denotes hydrogen;-   R² denotes hydrogen, fluorine, chlorine, or methyl; and-   R³ denotes methyl, ethyl, isopropyl, tert-butyl, OH, fluorine,    chlorine, bromine, methoxy, ethoxy, —O—CH₂—COOH, —O—CH₂—CH₂—COOH,    —O—CH₂—CH₂—CH₂—COOH, —O—CH₂—COOmethyl, —O—CH₂—COOethyl,    —O—CH₂—CH₂—COOmethyl, —O—CH₂—CH₂—COOethyl, —O—CH₂—CH₂—CH₂—COOmethyl,    or —O—CH₂—CH₂—CH₂—COOethyl.

Also particularly preferred are compounds of general formula 1 wherein

-   n denotes 1;-   R¹ denotes hydrogen;-   R² denotes hydrogen, fluorine, chlorine, or methyl; and-   R³ denotes OH, fluorine, chlorine, methyl, methoxy, ethoxy, or    —O—CH₂—COOH.

Other particularly preferred compounds of general formula 1 according tothe invention are those wherein

-   n denotes 1;-   R¹ denotes hydrogen;-   R² denotes halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl, preferably    fluorine, chlorine, methoxy, or methyl; and-   R³ denotes halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl, preferably    fluorine, chlorine, methoxy, or methyl.

Another preferred aspect of the present invention relates to thecompounds of general formula 1 wherein n is 1, R¹ and R² denotehydrogen, and the group R³ may have the abovementioned meanings.

Another preferred aspect of the present invention relates to thecompounds of general formula 1 wherein:

-   n denotes 1;-   R¹ and R² denote hydrogen; and-   R³ denotes methyl, ethyl, isopropyl, tert-butyl, OH, fluorine,    chlorine, bromine, methoxy, ethoxy, —O—CH₂—COOH, —O—CH₂—CH₂—COOH,    —O—CH₂—CH₂—CH₂—COOH, —O—CH₂—COOmethyl, —O—CH₂—COOethyl,    —O—CH₂—CH₂—COOmethyl, —O—CH₂—CH₂—COOethyl, —O—CH₂—CH₂—CH₂—COOmethyl,    or —O—CH₂—CH₂—CH₂—COOethyl.

Particularly preferred are compounds of general formula 1 wherein:

-   n denotes 1;-   R¹ and R² denote hydrogen; and-   R³ denotes OH, fluorine, chlorine, methoxy, ethoxy, or —O—CH₂—COOH,    preferably OH, fluorine, chlorine, ethoxy, or methoxy.

Particularly preferred are compounds of general formula 1 wherein:

-   n denotes 1;-   R¹ and R² denote hydrogen; and-   R³ denotes fluorine, chlorine, methoxy, or ethoxy.

The present invention also relates to compounds of general formula 1wherein:

-   n denotes 1;-   R¹ denotes hydrogen, halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl;-   R² denotes hydrogen, halogen, C₁-C₄-alkyl, or —O—C₁-C₄-alkyl; and-   R³ denotes hydrogen.

Also preferred are compounds of general formula 1 wherein:

-   n denotes 1;-   R¹ denotes hydrogen, fluorine, chlorine, methyl, or methoxy;-   R² denotes hydrogen, fluorine, chlorine, methyl, or methoxy; and-   R³ denotes hydrogen.

The present invention also relates to compounds of general formula 1wherein:

-   n denotes 1;-   R¹ denotes fluorine, chlorine, methyl, or methoxy;-   R² denotes fluorine, chlorine, methyl, or methoxy; and-   R³ denotes hydrogen.

In the compounds of formula 1, the groups R¹ and R², if they do notrepresent hydrogen, may each be arranged in the ortho or meta positionrelative to the bond to the benzylic “—CH₂” group. If neither of thegroups R¹ and R² denotes hydrogen, preferred compounds of formula 1 arethose wherein the two groups R¹ and R² are either in the orthoconfiguration or both groups R¹ and R² are in the meta configuration,while the use of those compounds wherein both groups R¹ and R² are inthe ortho configuration is particularly important.

In the compounds of formula 1 wherein one of the groups R¹ and R² doesnot denote hydrogen, it may be in the ortho or meta configuration withrespect to the bond to the benzylic “—CH₂” group. In this case,particularly preferred compounds of formula 1 are those wherein thegroup R¹ or R², which does not denote hydrogen, is in the orthoconfiguration.

Also particularly preferred are compounds of general formula 1 which areselected from among:

-   (1)    6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one;-   (2)    6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;-   (3) 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyacetic    acid)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;-   (4)    8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (5)    6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one;-   (6) 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1    dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one;-   (7)    8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (8)    8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (9)    8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (10)    8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (11)    8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (12)    8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (13)    8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (14)    4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methylpropyl}phenoxy)butyric    acid;-   (15)    8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (16)    8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (17)    8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (18)    8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (19)    8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (20)    8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (21)    8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (22)    8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (23)    8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (24)    8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (25)    8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (26)    8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (27)    8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (28)    8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (29)    8-{2-[2-(3,5-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (30)    8-{2-[2-(4-chloro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (31)    8-{2-[2-(3,4,5-trifluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;-   (32)    8-{2-[2-(3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    and-   (33)    8-{2-[2-(3,4-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one.

In another aspect, the present invention relates to the abovementionednew compounds of formula 1 in the form of the individual opticalisomers, mixtures of the individual enantiomers or racemates.Particularly preferred are compounds of formula 1 in the form of theenantiomerically pure compounds, while the R-enantiomers of thecompounds of formula 1 are of exceptional importance according to theinvention. Methods of separating racemates into the respectiveenantiomers are known in the prior art and may be used analogously toprepare the enantiomerically pure R- and S-enantiomers of the compoundsof formula 1.

In another aspect, the present invention relates to the abovementionedcompounds of formula 1 in the form of the acid addition salts withpharmacologically acceptable acids as well as optionally in the form ofthe solvates and/or hydrates thereof.

In another aspect, the present invention relates to the abovementionedcompounds of formula 1 for use as pharmaceutical compositions. Thepresent invention further relates to the use of the abovementioned newcompounds of general formula 1 for preparing a pharmaceuticalcomposition for the treatment of COPD. The present invention furtherrelates to the use of the abovementioned new compounds of generalformula 1 for preparing a pharmaceutical composition for the once-a-daytreatment of COPD.

Moreover, the present invention relates to a process for the treatmentof COPD, characterized in that one or more of the abovementionedcompounds of general formula 1 are administered in therapeuticallyeffective amounts. The present invention also relates to processes fortreating COPD, characterized in that one or more of the abovementionednew compounds of general formula 1 are administered once a day intherapeutically effective amounts.

By acid addition salts with pharmacologically acceptable acids aremeant, for example, the salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulfonate salts,preferably the hydrochloride, hydrobromide, hydrosulfate,hydrophosphate, hydrofumarate, and hydromethanesulfonate salts. Of theabovementioned acid addition salts, the salts of hydrochloric acid,methanesulfonic acid, benzoic acid, and acetic acid are particularlypreferred according to the invention.

For use according to the invention, the compounds of general formula 1may optionally be used in the form of their individual optical isomers,mixtures of the individual enantiomers or racemates. If the compoundsare used in enantiomerically pure form, the R-enantiomers are preferred.

Unless otherwise stated, the alkyl groups are straight-chained orbranched alkyl groups having 1 to 4 carbon atoms. The following arementioned by way of example: methyl, ethyl, propyl, or butyl. In somecases the abbreviations Me, Et, Prop, or Bu are used to denote thegroups methyl, ethyl, propyl, or butyl. Unless otherwise stated, thedefinitions propyl and butyl include all the possible isomeric forms ofthe groups in question. Thus, for example, propyl includes n-propyl andisopropyl, butyl includes isobutyl, sec-butyl, and tert-butyl, etc.

Unless otherwise stated, the alkylene groups are branched and unbrancheddouble-bonded alkyl bridges having 1 to 4 carbon atoms. The followingare mentioned by way of example: methylene, ethylene, n-propylene, orn-butylene. Unless otherwise stated, the term alkyloxy groups (or—O-alkyl groups) denotes branched and unbranched alkyl groups having 1to 4 carbon atoms which are linked via an oxygen atom. Examples of theseinclude: methyloxy, ethyloxy, propyloxy, or butyloxy. The abbreviationsMeO—, EtO—, PropO—, or BuO— are used in some cases to denote the groupsmethyloxy, ethyloxy, propyloxy, or butyloxy. Unless otherwise stated,the definitions propyloxy and butyloxy include all possible isomericforms of the groups in question. Thus, for example, propyloxy includesn-propyloxy and isopropyloxy, butyloxy includes isobutyloxy,sec-butyloxy, and tert-butyloxy, etc. In some cases, within the scope ofthe present invention, the term alkoxy is used instead of the termalkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy, or butoxy mayalso be used to denote the groups methyloxy, ethyloxy, propyloxy, orbutyloxy.

Halogen within the scope of the present invention denotes fluorine,chlorine, bromine, or iodine. Unless stated otherwise, fluorine,chlorine, and bromine are the preferred halogens.

The compounds according to the invention may be prepared analogously tomethods already known from the prior art. Suitable methods ofpreparation are known for example from U.S. Pat. No. 4,460,581, to theentire contents of which reference is made at this point.

The examples of synthesis described below serve to illustrate compoundsknown from the prior art, which may surprisingly be used according tothe present invention for the treatment of COPD.

EXAMPLE 16-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-2,6-dimethylphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one

The compound is known from U.S. Pat. No. 4,460,581.

EXAMPLE 28-{2-[1,1-dimethyl-3-phenylpropylamnio]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The compound is known from U.S. Pat. No. 4,460,581.

The examples of synthesis described below serve to illustrate newcompounds according to the invention more fully. They are intended onlyas examples of procedure to illustrate the invention without restrictingit to the subject matter described hereinafter.

EXAMPLE 36-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one

(a)8-{2-[1,1-dimethyl-2-(4-methoxyphenyl)ethylamino]-1-hydroxyethyl}-6-benzyloxy-4H-benzo[1,4]oxazin-3-one

7.5 g of (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)glyoxal hydrate is addedat 70° C. to a solution of 3.6 g of1,1-dimethyl-2-(4-methoxyphenyl)ethylamine in 100 mL ethanol and stirredfor 15 minutes. Then 1 g of sodium borohydride is added within 30minutes at 10° C. to 20° C. The mixture is stirred for one hour,combined with 10 mL acetone, and stirred for a further 30 minutes. Thereaction mixture is diluted with 150 mL ethyl acetate, washed withwater, dried with sodium sulfate, and evaporated down. The residue isdissolved in 50 mL methanol and 100 mL ethyl acetate and acidified withconcentrated hydrochloric acid. After the addition of 100 mL diethylether, the product precipitates out. The crystals are filtered off,washed, and recrystallized in 50 mL ethanol. Yield: 7 g (68%;hydrochloride); melting point: 232° C.-234° C.

(b)8-{2-[1,1-dimethyl-2-(4-methoxyphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

6.8 g of the benzyl compound obtained above are hydrogenated in 125 mLmethanol with the addition of 1 g palladium on charcoal (5%) at ambienttemperature and under normal pressure. The catalyst is filtered off andthe filtrate is freed from solvent. After recrystallization of theresidue in 50 mL acetone and some water, a solid is obtained, which isfiltered off and washed. Yield: 5.0 g (89%; hydrochloride); meltingpoint: 155° C.-160° C.

The (R)- and (S)-enantiomers of Example 3 may be obtained from theracemate, for example, by chiral HPLC (e.g., column: Chirobiotic T,250×22.1 mm made by Messrs Astec). The mobile phase may be methanol with0.05% triethylamine and 0.05% acetic acid. Silica gel with a particlesize of 5 μm, to which the glycoprotein Teicoplanin is covalently bound,can be used as the column material. Retention time (R-enantiomer): 40.1minutes; retention time (S-enantiomer): 45.9 minutes. Both enantiomersare obtained according to this method in the form of their free base.The R-enantiomer of Example 3 is of exceptional importance according tothe invention.

EXAMPLE 4 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one

(a) 8-{2-[1,1-dimethyl-2-(4-phenoxyethylacetate)ethylamino]-1-hydroxyethyl}-6-benzyloxy-4H-benzo[1,4]oxazin-3-one

The title compound is obtained analogously to the method described inExample 3(a) from 15 g of (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)glyoxalhydrate and 11.8 g of 1,1-dimethyl-2-(4-phenoxyethyl acetate)ethylaminehydrochloride. Yield: 16.5 g (69%, hydrochloride); melting point: 212°C.-214° C.

(b) 8-{2-[1,1-dimethyl-2-(4-phenoxyethylacetate)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

8 g of the benzyl alcohol obtained above is dissolved in 100 mL ethanol,100 mL methanol, and 10 mL water and hydrogenated in the presence of 1 gpalladium on charcoal (5%). After the theoretically calculated amount ofhydrogen has been taken up, the catalyst is filtered off and thefiltrate is evaporated down. The product which crystallizes out when thesolvent is distilled off is suction filtered and washed. Yield: 5.5 g(81%; hydrochloride); melting point: 137° C.-140° C.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 5 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyaceticacid)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one

11 g of8-{2-[1,1-dimethyl-2-(4-phenoxyethylacetate)ethylamino]-1-hydroxyethyl}-6-benzyloxy-4H-benzo[1,4]oxazin-3-onehydrochloride (Example 4(a)) is dissolved in 125 mL methanol andhydrogenated in the presence of 1 g palladium on charcoal (5%). Afterthe theoretically calculated amount of hydrogen has been taken up, thecatalyst is filtered off. 2.6 g of sodium hydroxide dissolved in 20 mLwater is added to the filtrate. The mixture is refluxed for 30 minutes,the methanol is distilled off and combined with 10 mL water, 20 mLn-butanol, and 3.9 mL acetic acid. The solid precipitated is suctionfiltered and washed with diethyl ether. Yield: 7 g (87%). Thehydrochloride is obtained by recrystallization from 0.5 molarhydrochloric acid. Melting point: 152° C.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 68-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a)1-(6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylimino]ethanone

7.2 g of (6-benzyloxy-4H-benzo[1,4]oxazin-3-one)glyoxal hydrate and 3.6g of 1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamine are heated to 70°C. for one hour in 100 mL ethanol. After cooling, the crystalsprecipitated are filtered off and washed with ethanol and diethyl ether.Yield: 8.6 g (94%); melting point: 175° C.

(b)8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-benzyloxy-4H-benzo[1,4]oxazin-3-one

8.6 g of the Schiff base obtained according to Example 6(a) is dissolvedin 100 mL ethanol and 20 mL THF, combined with 0.7 g sodium borohydridewithin 30 minutes at 10° C.-20° C., and stirred for one hour. After theaddition of 10 mL acetone, the mixture is stirred for 30 minutes andthen diluted with ethyl acetate and water. The product whichcrystallizes out on acidification with concentrated hydrochloric acid isfiltered off and washed. Yield: 7.4 g (80%, hydrochloride); meltingpoint: 235° C. (decomposition).

c)8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydro-4H-benzo[1,4]oxazin-3-one

7.4 g of the benzyl compound obtained according to Example 6(b) ishydrogenated in 125 mL methanol with the addition of 1 g palladium oncharcoal (5%) at ambient temperature under normal pressure. Then thecatalyst is filtered off and the filtrate is evaporated down. Theproduct which crystallizes out when acetone is added is suction filteredand washed with acetone and diethyl ether. Yield: 5 g (78%,hydrochloride); melting point 160° C. (decomposition).

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 76-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1′-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one

(a)8-{2-[1,1-dimethyl-2-(4-hydroxyphenyl)ethylamino]-1-hydroxyethyl}-6-benzyloxy-4H-benzo[1,4]oxazin-3-one

The title compound is prepared from 10 g of(6-benzyloxy-4H-benzo[1,4]oxazin-3-one)-glyoxal hydrate and 4.6 g of1,1-dimethyl-2-(4-hydroxyphenyl)ethylamine analogously to the method forExample 3(a). Yield: 9.0 g (64%, hydrochloride); melting point: 255°C.-258° C.

(b)8-{2-[1,1-dimethyl-2-(4-hydroxyphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

5.7 g of the coupling product obtained above are hydrogenated in thepresence of 0.6 g palladium on charcoal (5%) in 100 mL methanol. Afterthe theoretically calculated amount of hydrogen has been taken up, thecatalyst is filtered off and the filtrate is freed from solvent. Theresidue is dissolved in ethanol with heating and then combined withdiethyl ether. The product precipitated is suction filtered andrecrystallized once in water. Yield: 3.6 g (72%, hydrochloride); meltingpoint: 159° C.-162° C.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 86-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one

(a) 1-(4-isopropylphenyl)-2-methylpropan-2-ol

The reaction of a Grignard compound, prepared from 20 g (119 mmol)4-isopropylbenzyl chloride, with 11.4 mL (155 mmol) acetone yields thetarget compound as a colorless oil. Yield: 13.0 g (57%); massspectrometry: [M+H]⁺=193.

(b) N-[2-(4-isopropylphenyl)-1,1-dimethylethyl]acetamide

A Ritter reaction is carried out with 10.2 g (53 mmol) of1-(4-isopropylphenyl)-2-methylpropan-2-ol in the manner described forExample 9(b). The reaction mixture is poured onto ice water and madealkaline with sodium hydroxide solution, whereupon a solid isprecipitated. This is suction filtered and dried. Yield: 9.90 g (80%);mass spectrometry: [M+H]⁺=234.

(c) 2-(4-isopropylphenyl)-1,1-dimethylethyl amine

Reaction of 9.80 g (42 mmol) ofN-[2-(4-isopropylphenyl)-1,1-dimethylethyl]acetamide analogously to themethod for Example 9(c). Yield: 7.00 g (71%, hydrochloride); meltingpoint 202° C.-206° C.

(d)6-benzyloxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one

2.18 g (6.1 mmol) ofbenzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 1.1g (5.8 mmol) of 2-(4-isopropylphenyl)-1,1-dimethylethylamine are stirredin 40 mL ethanol at 50° C.-80° C. for one hour. After cooling to ambienttemperature, 0.24 g (6.3 mmol) sodium borohydride is added. The mixtureis stirred for one hour, diluted with 5 mL acetone, and stirred for afurther 30 minutes. The reaction mixture is acidified with hydrochloricacid, combined with 100 mL water and 80 mL ethyl acetate, and madealkaline with ammonia. The organic phase is separated off, dried withsodium sulfate, and freed from solvent. The residue is dissolved in 20mL ethyl acetate and 10 mL water, acidified with concentratedhydrochloric acid and diluted with diethyl ether. After the addition ofa crystallization aid, the solid precipitate is suction filtered andwashed. White solid. Yield: 1.7 g (52%, hydrochloride); melting point:220° C.-222° C.

(e)6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one

1.6 g (3.0 mmol) of6-benzyloxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-oneis dissolved in methanol and hydrogenated with palladium on charcoal ascatalyst at normal pressure and ambient temperature. The catalyst issuction filtered, the solvent distilled off, and the residuerecrystallized from isopropanol. White solid. Yield: 1.1 g (85%,hydrochloride); melting point 248° C.-250° C.; mass spectrometry:[M+H]⁺=399.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 98-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) 1-(4-ethylphenyl)-2-methylpropan-2-ol

14.8 g (90 mmol) of 1-(4-ethylphenyl)propan-2-one dissolved in diethylether is added dropwise to 39 mL of a 3 molar solution ofmethylmagnesium bromide in diethyl ether while being cooled with an icebath in such a way that the temperature does not exceed 30° C. After theaddition has ended, the reaction mixture is refluxed for 1.5 hours andthen hydrolyzed with 10% ammonium chloride solution. After the removalof the organic phase, the aqueous phase is extracted with diethyl ether.The combined ether phases are washed with water, dried with sodiumsulfate, and evaporated down. The oil thus obtained is further reacteddirectly. Yield: 15.5 g (90%).

(b) N-[2-(4-ethylphenyl)-1,1-dimethylethyl]acetamide

6.2 mL of concentrated sulfuric acid is added dropwise to 15.5 g (87mmol) of 1-(4-ethylphenyl)-2-methylpropan-2-ol in 4.8 mL (91 mmol)acetonitrile and 15 mL glacial acetic acid within 15 minutes, duringwhich time the temperature rises to 65° C. It is then stirred for onehour, diluted with ice water, and made alkaline with concentrated sodiumhydroxide solution. After another 30 minutes' stirring, the solidprecipitated is suction filtered and washed with water. The crudeproduct is dissolved in ethyl acetate, dried with sodium sulfate, andevaporated down. The oil remaining is combined with petroleum ether,whereupon a solid is precipitated which is filtered off and dried.Yield: 16.3 g (85%); melting point 90° C.-92° C.

(c) 2-(4-ethylphenyl)-1,1-dimethylethylamine

16.3 g (74 mmol) of N-[2-(4-ethylphenyl)-1,1-dimethylethyl]acetamide and8.0 g of potassium hydroxide are refluxed for 15 hours in 60 mL ethyleneglycol. The reaction mixture is combined with ice water and extractedthree times with diethyl ether. The combined organic phases are washedwith water, dried with sodium sulfate, and freed from solvent. Toprepare the hydrochloride, the crude product is dissolved inacetonitrile and ethereal hydrochloric acid and diethyl ether are addedsuccessively. The solid precipitated is suction filtered and dried.Yield: 11.0 g (69%, hydrochloride); melting point 165° C.-167° C.

(d)6-benzyloxy-8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one

The target compound is prepared analogously to the method for Example8(d) from 2.14 g (6.0 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and1.0 g (5.6 mmol) of 2-(4-ethylphenyl)-1,1-dimethylethylamine. Whitesolid. Yield: 1.7 g (54%, hydrochloride); melting point 210° C.-214° C.

(e)8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The hydrogenolysis of 1.45 g (2.75 mmol) of6-benzyloxy-8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-oneaccording to the method for Example 8(e) yields the target compound inthe form of a white solid. Yield: 1.07 g (92%; hydrochloride); meltingpoint 266° C.-269° C.; mass spectrometry: [M+H]⁺=385.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 108-{2-[2-(4-Fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) 1-fluoro-2-methyl-4-(2-methylpropenyl)benzene

100 mL of a 0.5 molar solution of 4-fluoro-3-methylphenylmagnesiumbromide in THF are combined with 4.7 mL (50 mmol) isopropylaldehydewithin 30 minutes, while the temperature rises to 45° C. The mixture isstirred for 30 minutes, refluxed for 1 hour, and then hydrolyzed with10% ammonium chloride solution. After separation of the organic phase,extraction is carried out with diethyl ether. The organic phases arecombined, dried, and evaporated down. The alcohol thus obtained isdissolved in 100 mL toluene, combined with 1 g of p-toluenesulfonic acidmonohydrate, and refluxed for three hours using the water separator. Thereaction mixture is poured onto water and made alkaline withconcentrated sodium hydroxide solution. After separation of the organicphase, it is washed with water, dried with sodium sulfate, and freedfrom solvent. Fractional distillation of the residue yields the productin the form of a colorless liquid (boiling point 80° C.-85° C./10 mbar).Yield: 4.1 g (50%).

(b) N-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethyl]formamide

4.9 mL concentrated sulfuric acid are added dropwise at 5° C.-15° C. to1.5 g (31 mmol) sodium cyanide in 5 mL glacial acetic acid. Then themixture is combined with 3.9 g (24 mmol) of1-fluoro-2-methyl-4-(2-methylpropenyl)benzene, dissolved in 10 mLglacial acetic acid, and stirred for 1 hour at 50° C.-60° C. Thereaction mixture is diluted with ice water, made alkaline withconcentrated sodium hydroxide solution, and extracted withdichloromethane. The organic phase is dried with sodium sulfate andfreed from solvents in vacuo. The slightly yellow oil thus obtained isfurther reacted directly. Yield: 4.3 g (87%).

(c) 2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamine

4.3 g (20.6 mmol) ofN-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethyl]formamide, 20 mLconcentrated hydrochloric acid, and 20 mL water are refluxed for 2hours. The reaction mixture is diluted with water, made alkaline withconcentrated sodium hydroxide solution, and extracted withdichloromethane. The organic phases are dried with sodium sulfate andevaporated down. The residue is dissolved in ethyl acetate, combinedwith ethereal hydrochloric acid, and cooled. The crystals precipitatedare suction filtered and washed with diethyl ether and dried. Whitesolid. Yield: 3.9 g (87%, hydrochloride); melting point 196° C.-198° C.

(d)6-benzyloxy-8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one

1.10 g (3.1 mmol) ofbenzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and0.50 g (2.8 mmol) of 2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamineare reacted and worked up analogously to the method for Example 8(d).White solid. Yield: 0.75 g (47%, hydrochloride); melting point 228°C.-230° C.

(e)8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The hydrogenation of 0.70 g (1.4 mmol) of6-benzyloxy-8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-oneyields the target compound as a white solid. Yield: 0.50 g (87%,hydrochloride); melting point 278° C.-280° C.; mass spectroscopy:[M+H]⁺=389.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 118-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) 1-(4-fluoro-2-methylphenyl)-2-methylpropyl acetate

500 mL of a 0.5 molar solution of 4-fluoro-6-methylphenylmagnesiumbromide and 23.2 mL (260 mmol) isopropylaldehyde are reacted analogouslyto Example 10(a). After hydrolysis with 10% ammonium chloride solution,the aqueous phase is separated off and extracted with diethyl ether. Thecombined organic phases are dried with sodium sulfate and evaporateddown. The alcohol thus obtained is then dissolved in 50 mL aceticanhydride, combined with 1 mL concentrated sulfuric acid, and refluxedfor three hours. Then the reaction mixture is poured onto water, stirredfor a further hour, and made alkaline. It is extracted withdichloromethane, the organic phases are dried with sodium sulfate, andthe solvents are distilled off. Fractional distillation of the residueyields the product in the form of a colorless liquid (boiling point:105° C.-110° C./8 mbar). Yield 29.0 g (52%).

(b) N-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethyl]formamide

29.0 g (130 mmol) of 1-(4-fluoro-2-methylphenyl)-2-methylpropyl acetateis reacted and worked up analogously to the method for Example 10(b).Yellow oil. Yield: 27.0 g (99%).

(c) 2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamine

In order to prepare the amine, 27.0 g (130 mmol) ofN-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethyl]formamide is reacted asdescribed in the method for Example 10(c). White solid. Yield: 15.5 g(55%, hydrochloride); melting point: 277° C.-280° C.

(d)6-benzyloxy-8-{2-[2-[4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one

Prepared analogously to the method for Example 8(d) from 0.95 g (2.66mmol) ofbenzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and0.43 g (2.37 mmol) of2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamine. Yield: 0.75 g (55%,hydrochloride); melting point 233° C.-236° C.

(e)8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The debenzylation of 0.70 g (1.36 mmol) of6-benzyloxy-8-{2-[2-[4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-oneyields the target compound in the form of a white solid. Yield: 0.50 g(87%, hydrochloride); melting point 278° C.-280° C.; mass spectroscopy:[M+H]⁺=389.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 128-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) 1-(2,4-difluorophenyl)-2-methylpropan-2-ol

11.0 mL acetone, diluted with 50 mL diethyl ether, is added dropwise toa solution of 500 mL of 0.25 molar 2,4-difluorobenzylmagnesium bromidein diethyl ether within 20 minutes. Then the mixture is refluxed for 1.5hours and then hydrolyzed with 10% ammonium chloride solution. The etherphase is separated off, washed with water, dried with sodium sulfate,and evaporated down. The fractional distillation of the residue yieldsthe alcohol as a colorless liquid (boiling point: 70° C.-73° C./2mmbar). Yield: 20.0 g (86%).

(b) N-[2-(2,4-difluorophenyl]-1,1-dimethylethyl]formamide

Ritter reaction with 20 g (110 mmol) of1-(2,4-difluorophenyl)-2-methylpropan-2-ol according to the methoddescribed for Example 10(b). Yellow oil. Yield: 22.0 g (94%).

(c) 2-(2,4-difluorophenyl)-1,1-dimethylethylamine

Reaction of 22.0 g (100 mmol) ofN-[2-(2,4-difluorophenyl]-1,1-dimethylethyl]formamide analogously to themethod for Example 10(c). Yield: 16.0 g (72%, hydrochloride); meltingpoint: 201° C.-203° C.

(d)6-benzyloxy-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one

Reaction of 0.89 g (2.49 mmol) ofbenzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and0.40 g (2.16 mmol) of 2-(2,4-difluorophenyl)-1,1-dimethylethylamine inthe manner described for Example 8(d). Yield: 0.80 g (62%,hydrochloride); melting point 245° C.-247° C.

(e)8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The hydrogenolysis of 0.70 g (1.35 mmol) of6-benzyloxy-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-oneyields the target compound as a white solid. Yield: 0.48 g (83%,hydrochloride); melting point 279° C.-280° C.; mass spectroscopy:[M+H]⁺=393.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 138-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) 1-(3,5-difluorophenyl)-2-methylpropan-2-ol

The target compound is obtained by reacting a Grignard compound,prepared from 25.0 g (121 mmol) of 3,5-difluorobenzyl bromide, with 12.6mL (171 mmol) of acetone. Yellow oil. Yield: 13.5 g (60%).

(b) 2-(3,5-difluorophenyl)-1,1-dimethylethylamine

The Ritter reaction of 5.5 g (29.5 mmol) of1-(3,5-difluorophenyl)-2-methylpropan-2-ol and 1.8 g of sodium cyanideyields 7.0 g of formamide, which is treated with hydrochloric acid tocleave the formyl group. Slightly yellow oil. Yield: 4.6 g (75%).

(c)6-benzyloxy-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one

Prepared from 1.73 g (4.84 mmol) ofbenzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and0.80 g (4.32 mmol) of 2-(3,5-difluorophenyl)-1,1-dimethylethylamine inthe usual way. Yield: 1.50 g (58%, hydrochloride); melting point: 240°C.-244° C.

(d)8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

Hydrogenolysis of 1.30 g (2.43 mmol) of6-benzyloxy-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-oneyields the target compound as a white solid. Yield: 0.90 g (86%,hydrochloride); melting point 150° C.-158° C.; mass spectroscopy:[M+H]⁺=393.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 148-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) benzyl [2-(4-ethoxyphenyl)-1,1-dimethylethyl]carbaminate

15.0 g (50 mmol) of benzyl[2-(4-hydroxyphenyl)-1,1-dimethylethyl]carbaminate is stirred with 7.5mL (92 mmol) ethyl iodide and 21 g (150 mmol) potassium carbonate for 10hours at 90° C.-100° C. The reaction mixture is combined with ethylacetate, washed twice with water, and dried with sodium sulfate. Afterthe solvents have been distilled off, a yellow oil remains (15.0 g,92%), which is further reacted directly.

(b) 2-(4-ethoxyphenyl)-1,1-dimethylethylamine

A solution of 15.0 g (49 mmol) benzyl[2-(4-ethoxyphenyl)-1,1-dimethylethyl]-carbaminate in 100 mL glacialacetic acid is combined with 2 g palladium on charcoal (10%) and thenhydrogenated at 5 bar and 40° C. to 50° C. The catalyst is filtered offand the filtrate is freed from solvent. The residue is dissolved in alittle water, made alkaline with concentrated sodium hydroxide solution,and extracted with ethyl acetate. The organic phase is washed withwater, dried with sodium sulfate, and evaporated down. The crude productis dissolved in acetonitrile and acidified with ethereal hydrochloricacid. The solid precipitated after the addition of diethyl ether issuction filtered and dried. Yield: 8.8 g (hydrochloride, 84%); meltingpoint 198° C.-200° C.

(c)6-benzyloxy-8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one

2.14 g (6.0 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and1.0 g (5.2 mmol) of 2-(4-ethoxyphenyl)-1,1-dimethylethylamine arestirred in 40 mL ethanol for one hour at 50° C.-80° C. After cooling toambient temperature, 0.23 g (6.0 mmol) of sodium borohydride are addedand the mixture is stirred for a further hour. The reaction mixture iscombined with 5 mL acetone, stirred for 30 minutes, acidified withglacial acetic acid, and evaporated down. The residue is combined withwater and ethyl acetate and made alkaline. The organic phase isseparated off, washed with water, dried with sodium sulfate, and freedfrom solvent in vacuo. The residue is dissolved again in ethyl acetateand water, combined with concentrated hydrochloric acid, and dilutedwith diethyl ether. The solid precipitated is suction filtered andwashed with diethyl ether. White solid. Yield: 2.0 g (61%,hydrochloride); melting point: 214° C.-216° C.

(d)8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

1.5 g (2.8 mmol) of6-benzyloxy-8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-onein 80 mL methanol are hydrogenated with 250 mg palladium on charcoal(10%) as catalyst at ambient temperature and normal pressure. Thecatalyst is suction filtered and the filtrate is evaporated down. Theresidue is dissolved in 5 mL ethanol by heating, seeded, and dilutedwith ethyl acetate. The solid precipitated is filtered off and washed.White solid. Yield 1.0 g (83%, hydrochloride); melting point: 232°C.-235° C.; mass spectrometry: [M+H]⁺=401.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 158-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) 1-(3,5-dimethylphenyl)-2-methylpropanol-2-ol

Obtained by reacting ethyl (3,5-dimethylphenyl)acetate withmethylmagnesium bromide.

(b) 2-(3,5-dimethylphenyl)-1,1-dimethylethylamine

By reacting 6.00 g (34 mmol) of1-(3,5-dimethylphenyl)-2-methylpropanol-2-ol and 2.00 g (41 mmol) ofsodium cyanide in a Ritter reaction, 2.40 g of2-(3,5-dimethylphenyl)-1,1-dimethylethylformamide (35% yield) isobtained. To liberate the amine, the formamide (2.40 g, 11.7 mmol) istreated with hydrochloric acid. The method and working up are analogousto the method for Example 10(c). Oil. Yield: 1.70 g (82%); massspectroscopy: [M+H]⁺=178.

(c)6-benzyloxy-8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one

Prepared analogously to the method for Example 8(d) from 1.47 g (4.1mmol) ofbenzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and0.65 g (3.7 mmol) of 2-(3,5-dimethylphenyl)-1,1-dimethylethylamine.Yield: 1.1 g (51%, hydrochloride); melting point: 220° C.-222° C.

(d)8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The target compound was obtained after hydrogenolysis of 0.90 g (1.71mmol) of6-benzyloxy-8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-oneand recrystallization of the crude product from isopropanol. Whitesolid. Yield: 0.50 g (69%, hydrochloride); melting point: 235° C.-238°C.; mass spectroscopy: [M+H]⁺=385.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 164-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-2-methylpropyl}phenoxy)butyricacid

(a) ethyl 4-[4-(2-amino-2-methylpropyl)-phenoxy]-butyrate

4.5 g (15.0 mmol) of benzyl[2-(4-hydroxyphenyl)-1,1-dimethylethyl]carbaminate, 2.3 mL (16.0 mmol)of ethyl 4-bromobutyrate, 2.3 g (16.6 mmol) of potassium carbonate, and0.3 g (1.8 mmol) of potassium iodide in 20 mL dimethylformamide areheated to 120° C. for 13 hours. The reaction mixture is diluted withethyl acetate and washed successively with water, sodium hydroxidesolution, and water. The organic phase is dried with sodium sulfate andevaporated down. The residue is purified by chromatography (eluent:cyclohexane-ethyl acetate (9:1)). 5.0 g of a yellow oil is isolatedwhich is dissolved in 50 mL acetic acid and hydrogenated with 1.0 gpalladium on charcoal as catalyst at 40° C. and 3 bar. The catalyst isfiltered off and the filtrate is freed from solvent. The residue isdissolved in diethyl ether and combined with ethereal hydrochloric acid.The solid precipitated is suction filtered and dried. Yield: 2.9 g (66%in two stages, hydrochloride); melting point: 103° C.-105° C.

(b) ethyl4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyrate

1.20 g (3.36 mmol) ofbenzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and0.90 g (3.22 mmol) of ethyl4-[4-(2-amino-2-methylpropyl)phenoxy]butyrate are reacted in the mannerdescribed for Example 8(d). The crude product is dissolved in 10 mLethyl acetate and 10 mL water and combined with oxalic acid withstirring. The solution is diluted with diethyl ether and the solidprecipitated is suction filtered and washed with diethyl ether. Yield:1.20 g (54%, oxalate); melting point 223° C.-227° C.

(c)4-(4-[2-{2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyricacid

A solution of 1.00 g (1.73 mmol) of ethyl4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyratein 25 mL methanol is combined with 2.5 mL of 1 N sodium hydroxidesolution, refluxed for 30 minutes, and then neutralized with 1 Nhydrochloric acid. The solution is evaporated down and the residual oilis dissolved by heating in 5 mL of n-butanol. After the addition of acrystallization aid, a solid is precipitated out which is suctionfiltered and washed with acetone and diethyl ether. Yield: 0.75 g (79%);melting point: 216° C.-218° C.

(d)4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methylpropyl}phenoxy)butyricacid

0.70 g (1.28 mmol) of4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyricacid is dissolved in 25 mL methanol and 2 mL acetic acid andhydrogenated in the presence of 150 mg palladium on charcoal (10%) atambient temperature and normal pressure. The catalyst is filtered offand the filtrate is freed from solvent. The product is obtained bycrystallization from a methanol-acetone mixture. Yield: 0.40 g (68%);melting point: 201° C.-204° C.; mass spectroscopy: [M+H]⁺=459.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 178-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) 1-(3,4-difluorophenyl)-2-methylpropan-2-ol

From 23.0 g (111 mmol) of 3,4-difluorobenzyl bromide a Grignard isprepared, which is then reacted with 11.6 mL (158 mmol) of acetone.Slightly yellow oil. Yield: 9.7 g (47%); R_(f) value: 0.55 (ethylacetate-petroleum ether (1:3)).

(b) N-[2-(3,4-difluorophenyl)-1,1-dimethylethyl]formamide

The target compound is obtained by a Ritter reaction with 4.0 g (21.5mmol) of 1-(3,4-difluorophenyl)-2-methylpropan-2-ol. Slightly yellowoil. Yield: 4.0 g (87%); mass spectrometry: [M+H]⁺=214.

(c) 2-(3,4-difluorophenyl)-1,1-dimethylethylamine

4.00 g (18.5 mmol) ofN-[2-(3,4-difluorophenyl)-1,1-dimethylethyl]formamide is dissolved inethanol, combined with concentrated hydrochloric acid, and refluxedovernight. The reaction solution is poured onto ice water, made alkalinewith sodium hydroxide, and extracted with tert-butylmethyl ether. Theorganic phases are washed with water, dried with sodium sulfate, andevaporated down. Yellow oil. Yield: 3.2 g (92%); mass spectrometry:[M+H]⁺=186.

(d)8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and185 mg (1 mmol) of 2-(3,4-difluorophenyl)-1,1-dimethylethylamine arestirred for 30 minutes in 5 mL tetrahydrofuran at ambient temperature.It is cooled to 0° C. and, under an argon atmosphere, 1.5 mL of a 2molar solution of lithium borohydride in tetrahydrofuran is addeddropwise. The mixture is stirred for 30 minutes at ambient temperature,combined with 10 mL dichloromethane, and 3 mL water, stirred for afurther hour and then filtered through an EXTRELUT® column. The eluatecontaining the ethanol amine is freed from solvent. The residue isdissolved in methanol and hydrogenated with palladium on charcoal (10%)as catalyst at 2.5 bar and ambient temperature. Then the catalyst isseparated off and the crude product is purified by chromatography. Whitesolid. Yield: 31 mg (6%, trifluoroethyl acetate); mass spectroscopy:[M+H]⁺=393.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 188-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

(a) 1-(2-chloro-4-fluorophenyl)-2-methylpropan-2-ol

Prepared from 20 g (97 mmol) of methyl (2-chloro-4-fluorophenyl)acetateand 98 mL of a 3 molar solution of methylmagnesium bromide analogouslyto the method for Example 8(a).

(b) N-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethyl]formamide

7.5 g (37 mmol) of 1-(2-chloro-4-fluorophenyl)-2-methylpropan-2-ol wasreacted and worked up according to the method described for Example10(b). The oil thus obtained was chromatographed for furtherpurification on a short silica gel column (petroleum ether-ethyl acetate(9:1)). Oil. Yield 7.4 g (87%); mass spectrometry: [M+H]⁺=230/232.

(c) 2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamine

Reaction of 7.4 g (32 mmol) ofN-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethyl]-formamide as describedin the method for Example 17(c). Brown oil. Yield: 5.14 g (79%); massspectrometry: [M+H]⁺=202/204.

(d)8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

357 mg (1 mmol) of6-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and202 mg (1 mmol) of 2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamineare reacted with lithium borohydride analogously to the method forExample 10(d). To debenzylate the ethanolamine thus obtained, it isdissolved in 3 mL of dichloromethane and cooled to −78° C. At thistemperature, 2 mL of a 1 molar solution of boron tribromide indichloromethane is added and the mixture is slowly allowed to come up toambient temperature. The reaction mixture is combined with 10 mLdichloromethane and 3 mL water and filtered through an EXTRELUT® column.The eluate is freed from solvent and the residue is purified bychromatography. White solid. Yield: 70 mg (13%, trifluoroethyl acetate);mass spectroscopy: [M+H]⁺=409/11.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 198-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

A solution of 300 mg (0.91 mmol) of6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 200mg (1.09 mmol) of 2-(4-chlorophenyl)-1,1-dimethylethylamine in 3 mLethanol was combined with molecular sieve and stirred for 90 minutes at80° C. It was allowed to cool to ambient temperature, 35 mg (0.91 mmol)of sodium borohydride was added, and the mixture was stirred for 1 hour.Then the reaction mixture was combined with sodium hydrogen carbonatesolution and extracted with ethyl acetate. The combined organic phaseswere freed from solvent and the residue was chromatographed (eluent:hexane-ethyl acetate-methanol), yielding 305 mg of ethanolamine. Thiswas dissolved in 3 mL dichloromethane and cooled to −78° C. under anargon atmosphere. 3 mL of a 1 molar solution of boron tribromide indichloromethane were added dropwise and the mixture was stirred for onehour at −78° C. and for 20 minutes at ambient temperature. Then at −78°C., 3 mL of concentrated ammonia solution was added dropwise and themixture was stirred for 5 minutes. The reaction mixture was combinedwith ammonium chloride solution and extracted with ethyl acetate. Thecombined organic phases were evaporated down and the residue was furtherpurified by chromatography (silica gel; eluent:dichloromethane-methanol+1% ammonia). Beige-colored solid: 93 mg (26%);mass spectrometry: [M+H]⁺=391.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 208-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The preparation of the ethanolamine and debenzylation were carried outas described in Example 19 from 300 mg (0.91 mmol) of6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 250mg (1.09 mmol) of 2-(4-bromophenyl)-1,1-dimethylethylamine. Beige solid.Yield: 54 mg (14%); mass spectrometry: [M+H]⁺=435, 437.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

EXAMPLE 218-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

300 mg (0.91 mmol) of6-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 183 mg(1.09 mmol) of 2-(4-fluorophenyl)-1,1-dimethylethylamine were dissolvedin 3 mL of ethanol. Molecular sieve was added and the mixture was heatedto 80° C. for 30 minutes. After cooling to ambient temperature, 35 mg(0.91 mmol) of sodium borohydride was added. The mixture was stirred for1 hour at ambient temperature, then sodium hydrogen carbonate solutionwas added to the reaction mixture and it was extracted with ethylacetate. The organic phases were evaporated down and the residue waschromatographed (eluent: hexane-ethyl acetate-methanol). Theethanolamine thus obtained (223 mg) was dissolved in methanol to cleavethe benzyl protecting group and hydrogenated with 150 mg palladiumhydroxide as catalyst at ambient temperature and normal pressure. Thecatalyst was separated off by filtering through CELITE® filter agent,the filtrate was freed from solvent and the residue was chromatographed(silica gel; eluent: dichloromethane-methanol). Beige solid. Yield: 76mg (22%); mass spectrometry: [M+H]⁺=375.

The (R)- and (S)-enantiomers of this example can be obtained byseparating the racemate analogously to current methods of racematecleaving known in the prior art.

The following compounds of Formula 1 according to the invention may beobtained analogously to the synthesis examples described above:

EXAMPLE 228-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 238-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 248-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 258-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 268-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 278-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 288-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 298-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 308-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 318-{2-[2-(3,5-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 328-{2-[2-(4-chloro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 338-{2-[2-(3,4,5-trifluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneEXAMPLE 348-{2-[2-(3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;and EXAMPLE 358-{2-[2-(3,4-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The compounds of general formula 1 may be used on their own or combinedwith other active substances of formula 1 according to the invention.The compounds of general formula 1 may optionally also be combined withother pharmacologically active substances. These include, in particular,anticholinergics, optionally other betamimetics, antiallergic agents,PDE-IV inhibitors, PAF-antagonists, leukotriene-antagonists, andcorticosteroids and combinations of these active substances.

Examples of preferred anticholinergics which may be mentioned includeipratropium, oxitropium, and tiotropium salts. Pharmaceuticalcombinations which contain the abovementioned salts, in addition to thecompounds of formula 1 according to the invention, preferably containthose salts of ipratropium, oxitropium, or tiotropium wherein the anionis selected from among the chloride, bromide, iodide, sulfate,phosphate, methanesulfonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate, andp-toluenesulfonate, optionally in the form of one of the solvates orhydrates thereof.

Within the scope of the present invention, the corticosteroids which mayoptionally be used in conjunction with the compounds of formula 1 may becompounds selected from among flunisolide, beclomethasone,triamcinolone, budesonide, fluticasone, mometasone, ciclesonide,rofleponide, and dexamethasone. In some cases, within the scope of thepresent patent application, the term steroids is used on its own insteadof the word corticosteroids. Any reference to steroids within the scopeof the present invention includes a reference to salts or derivativeswhich may be formed from the steroids. Examples of possible salts orderivatives include: sodium salts, sulfobenzoates, phosphates,isonicotinates, acetates, propionates, dihydrogen phosphates,palmitates, pivalates, or furoates. In some cases, the corticosteroidsmay also occur in the form of their hydrates.

Within the scope of the present invention, the term dopamine agonists,which may optionally be used in conjunction with the compounds offormula 1, denotes compounds selected from among bromocriptine,cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol,roxindole, ropinirole, talipexole, terguride, and viozan. Any referenceto the abovementioned dopamine agonists also includes, within the scopeof the present invention, a reference to any pharmacologicallyacceptable acid addition salts and hydrates thereof which may exist. Bythe physiologically acceptable acid addition salts thereof which may beformed by the abovementioned dopamine agonists are meant, for example,pharmaceutically acceptable salts selected from among the salts ofhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid, and maleic acid.

Examples of antiallergic agents which may be used according to theinvention as a combination with the compound of formula 1 includeepinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifene, emedastine, dimetindene,clemastine, bamipine, hexachloropheniramine, pheniramine, doxylamine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratadine, and meclizine. Any reference to theabovementioned antiallergic agents also includes, within the scope ofthe present invention, a reference to any pharmacologically acceptableacid addition salts thereof which may exist.

Examples of PDE-IV inhibitors which may be used according to theinvention as a combination with the compound of formula 1 includecompounds selected from among enprofylline, roflumilast, ariflo,Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A, andAWD-12-281. Any reference to the abovementioned PDE-IV inhibitors alsoincludes, within the scope of the present invention, a reference to anypharmacologically acceptable acid addition salts thereof which mayexist. By the physiologically acceptable acid addition salts which maybe formed by the abovementioned PDE-IV inhibitors are meant, forexample, pharmaceutically acceptable salts selected from among the saltsof hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid, and maleic acid. According to theinvention, the salts selected from among the acetate, hydrochloride,hydrobromide, sulfate, phosphate, and methanesulfonate are preferred inthis context.

Suitable preparations for administering the compounds of formula 1include, for example, tablets, capsules, suppositories, solutions,powders, etc. The content of the pharmaceutically active compound(s)should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-%of the composition as a whole. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate, orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example, collidone or shellac, gum arabic, talc, titaniumdioxide, or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavor enhancer,e.g., a flavoring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions are prepared in the usual way, e.g. with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates or stabilizerssuch as alkali metal salts of ethylenediaminetetraacetic acid,optionally using emulsifiers and/or dispersants, while if water is usedas diluent, for example, organic solvents may optionally be used assolubilizers or dissolving aids, and the solutions may be transferredinto injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may, for example, be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.,petroleum fractions), vegetable oils (e.g., groundnut or sesame oil),mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carrierssuch as, e.g., natural mineral powders (e.g., kaolins, clays, talc,chalk), synthetic mineral powders (e.g., highly dispersed silicic acidand silicates), sugars (e.g., cane sugar, lactose and glucose),emulsifiers (e.g., lignin, spent sulfite liquors, methylcellulose,starch, and polyvinylpyrrolidone) and lubricants (e.g., magnesiumstearate, talc, stearic acid, and sodium lauryl sulfate).

For oral use, the tablets may obviously contain, in addition to thecarriers specified, additives such as sodium citrate, calcium carbonate,and dicalcium phosphate together with various additional substances suchas starch, preferably potato starch, gelatin, and the like. Lubricantssuch as magnesium stearate, sodium lauryl sulfate, and talc may also beused to produce the tablets. In the case of aqueous suspensions, theactive substances may be combined with various flavor enhancers orcolorings in addition to the above-mentioned excipients.

For administering the compounds of formula 1 for the treatment of COPD,it is particularly preferred according to the invention to usepreparations or pharmaceutical formulations which are suitable forinhalation. Inhalable preparations include inhalable powders,propellant-containing metered-dose aerosols, or propellant-freeinhalable solutions. Within the scope of the present invention, the termpropellant-free inhalable solutions also includes concentrates orsterile inhalable solutions ready for use. The formulations which may beused within the scope of the present invention are described in moredetail in the next part of the specification.

The inhalable powders which may be used according to the invention maycontain 1 either on its own or in admixture with suitablephysiologically acceptable excipients.

If the active substances 1 are present in admixture with physiologicallyacceptable excipients, the following physiologically acceptableexcipients may be used to prepare these inhalable powders according tothe invention: monosaccharides (e.g., glucose or arabinose),disaccharides (e.g., lactose, saccharose, or maltose), oligo- andpolysaccharides (e.g., dextrans), polyalcohols (e.g., sorbitol,mannitol, or xylitol), salts (e.g., sodium chloride or calciumcarbonate) or mixtures of these excipients. Preferably, mono- ordisaccharides are used, while the use of lactose or glucose ispreferred, particularly, but not exclusively, in the form of theirhydrates. For the purposes of the invention, lactose is the particularlypreferred excipient, while lactose monohydrate is most particularlypreferred.

Within the scope of the inhalable powders according to the invention theexcipients have a maximum average particle size of up to 250 μm,preferably between 10 μm and 150 μm, most preferably between 15 μm and80 μm. It may sometimes seem appropriate to add finer excipientfractions with an average particle size of 1 μm to 9 μm to the excipientmentioned above. These finer excipients are also selected from the groupof possible excipients listed hereinbefore. Finally, in order to preparethe inhalable powders according to the invention, micronised activesubstance 1, preferably with an average particle size of 0.5 μm to 10μm, more preferably from 1 μm to 5 μm, is added to the excipientmixture. Processes for producing the inhalable powders according to theinvention by grinding and micronizing and finally mixing the ingredientstogether are known from the prior art.

The inhalable powders according to the invention may be administeredusing inhalers known from the prior art.

The inhalation aerosols containing propellant gas according to theinvention may contain the compounds 1 dissolved in the propellant gas orin dispersed form. The compounds 1 may be contained in separateformulations or in a common formulation, in which the compounds 1 areeither both dissolved, both dispersed or in each case only one componentis dissolved and the other is dispersed. The propellant gases which maybe used to prepare the inhalation aerosols are known from the prior art.Suitable propellant gases are selected from among hydrocarbons such asn-propane, n-butane, or isobutane and halohydrocarbons such asfluorinated derivatives of methane, ethane, propane, butane,cyclopropane, or cyclobutane. The abovementioned propellant gases may beused on their own or mixed together. Particularly preferred propellantgases are halogenated alkane derivatives selected from TG134a and TG227and mixtures thereof.

The propellant-driven inhalation aerosols may also contain otheringredients such as co-solvents, stabilizers, surfactants, antioxidants,lubricants, and pH adjusters. All these ingredients are known in theart.

The propellant-driven inhalation aerosols according to the inventionmentioned above may be administered using inhalers known in the art,such as metered dose inhalers (MDIs).

Moreover, the active substances 1 according to the invention may beadministered in the form of propellant-free inhalable solutions andsuspensions. The solvent used may be an aqueous or alcoholic, preferablyan ethanolic solution. The solvent may be water on its own or a mixtureof water and ethanol. The relative proportion of ethanol compared withwater is not limited but the maximum is preferably up to 70 percent byvolume, more particularly up to 60 percent by volume and most preferablyup to 30 percent by volume. The remainder of the volume is made up ofwater. The solutions or suspensions containing 1 are adjusted to a pH of2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjustedusing acids selected from inorganic or organic acids. Examples ofparticularly suitable inorganic acids include hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, and/or phosphoric acid.Examples of particularly suitable organic acids include ascorbic acid,citric acid, malic acid, tartaric acid, maleic acid, succinic acid,fumaric acid, acetic acid, formic acid, and/or propionic acid etc.Preferred inorganic acids are hydrochloric and sulfuric acids. It isalso possible to use the acids which have already formed an acidaddition salt with one of the active substances. Of the organic acids,ascorbic acid, fumaric acid and citric acid are preferred. If desired,mixtures of the above acids may be used, particularly in the case ofacids which have other properties in addition to their acidifyingqualities, e.g., as flavorings, antioxidants or complexing agents, suchas citric acid or ascorbic acid, for example. According to theinvention, it is particularly preferred to use hydrochloric acid toadjust the pH.

If desired, the addition of edetic acid (EDTA) or one of the known saltsthereof, sodium edetate, as stabilizer or complexing agent may beomitted in these formulations. Other embodiments may contain thiscompound or these compounds. In a preferred embodiment the content basedon sodium edetate is less than 100 mg/100 mL, preferably less than 50mg/100 mL, more preferably less than 20 mg/100 mL. Generally, inhalablesolutions in which the content of sodium edetate is from 0 to 10 mg/100mL are preferred.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions. Preferred co-solvents are those which containhydroxyl groups or other polar groups, e.g., alcohols, particularlyisopropyl alcohol, glycols, particularly propyleneglycol,polyethyleneglycol, polypropyleneglycol, glycol ether, glycerol,polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Theterms excipients and additives in this context denote anypharmacologically acceptable substance which is not an active substancebut which can be formulated with the active substance or substances inthe physiologically suitable solvent in order to improve the qualitativeproperties of the active substance formulation. Preferably, thesesubstances have no pharmacological effect or, in connection with thedesired therapy, no appreciable or at least no undesirablepharmacological effect. The excipients and additives include, forexample, surfactants such as soya lecithin, oleic acid, sorbitan esters,such as polysorbates, polyvinylpyrrolidone, other stabilizers,complexing agents, antioxidants and/or preservatives which guarantee orprolong the shelf life of the finished pharmaceutical formulation,flavorings, vitamins and/or other additives known in the art. Theadditives also include pharmacologically acceptable salts such as sodiumchloride as isotonic agents.

The preferred excipients include antioxidants such as ascorbic acid, forexample, provided that it has not already been used to adjust the pH,vitamin A, vitamin E, tocopherols, and similar vitamins and provitaminsoccurring in the human body.

Preservatives may be used to protect the formulation from contaminationwith pathogens. Suitable preservatives are those which are known in theart, particularly cetyl pyridinium chloride, benzalkonium chloride, orbenzoic acid or benzoates such as sodium benzoate in the concentrationknown from the prior art. The preservatives mentioned above arepreferably present in concentrations of up to 50 mg/100 mL, morepreferably between 5 and 20 mg/100 mL.

Preferred formulations contain, in addition to the solvent water and theactive substance 1, only benzalkonium chloride and sodium edetate. Inanother preferred embodiment, no sodium edetate is present.

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated. When administered by inhalation, the compounds offormula 1 are characterized by a high potency even at doses in the μgrange. The compounds of formula 1 may also be used effectively above theμg range. The dosage may then be in the gram range, for example.

In another aspect, the present invention relates to the above-mentionedpharmaceutical formulations as such which are characterized in that theycontain a compound of formula 1, particularly the above-mentionedpharmaceutical formulations which can be administered by inhalation.

The following examples of formulations illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations A. Tablets per tablet activesubstance 1 100 mg lactose 140 mg maize starch 240 mgpolyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500 mg

The finely ground active substance, lactose, and some of the maizestarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet granulated,and dried. The granules, the remaining maize starch and the magnesiumstearate are screened and mixed together. The mixture is pressed intotablets of suitable shape and size. B. Tablets per tablet activesubstance 1 80 mg lactose 55 mg maize starch 190 mg microcrystallinecellulose 35 mg polyvinylpyrrolidone 15 mg sodium carboxymethyl starch23 mg magnesium stearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose, and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size. C.Ampoule Solution active substance 1 50 mg sodium chloride 50 mg waterfor inj. 5 mL

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make the solutionisotonic. The resulting solution is filtered to remove pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilized and heat-sealed. The ampoules contain 5 mg, 25 mg, and50 mg of active substance. D. Metering Aerosol active substance 1 0.005sorbitan trioleate 0.1 monofluorotrichloromethane and to 100TG134a:TG227 (2:1)

The suspension is transferred into a conventional aerosol container withmetering valve. Preferably 50 μl suspension are released on eachactuation. The active substance may also be released in higher doses ifdesired (e.g., 0.02 wt.-%). E. Solutions (in mg/100 mL) active substance1 333.3 mg benzalkonium chloride  10.0 mg EDTA  50.0 mg HCl (1 N) to pH3.4

This solution can be prepared in the usual way. F. Inhalable Powderactive substance 1 12 μg lactose monohydrate to 25 mg

The inhalable powder is prepared in the usual way by mixing theindividual ingredients.

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 26. A method for the treatment of COPD comprising administration of a therpeutically effective amount of a compound of formula 1

wherein: n is 1 or 2; R¹ is hydrogen, C₁-C₄-alkyl, halogen, OH, or —O—C₁-C₄-alkyl; R² is hydrogen, C₁-C₄-alkyl, halogen, OH, or —O—C₁-C₄-alkyl; R³ is hydrogen, C₁-C₄-alkyl, OH, halogen, —O—C₁-C₄-alkyl, —O—C₁-C₄-alkylene-COOH, or —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof; and a pharmaceutically acceptable excipient or carrier.
 27. The method according to claim 1, wherein: R¹ is hydrogen, halogen or C₁-C₄-alkyl; R² is hydrogen, halogen, or C₁-C₄-alkyl; and R³ is hydrogen, C₁-C₄-alkyl, OH, halogen, —O—C₁-C₄-alkyl, —O—C₁-C₄-alkylene-COOH, or —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl.
 28. The method according to claim 1, wherein: R¹ is hydrogen, fluorine, chlorine, or methyl; R² is hydrogen, fluorine, chlorine, or methyl; and R³ is hydrogen, C₁-C₄-alkyl, OH, fluorine, chlorine, bromine, —O—C₁-C₄-alkyl, —O—C₁-C₄-alkylene-COOH, or —O—C₁-C₄-alkylene-CO—O—C₁-C₄-alkyl.
 29. The method according to claim 1, wherein: R¹ is hydrogen, methyl, or ethyl; R² is hydrogen, methyl, or ethyl; and R³ is hydrogen, methyl, ethyl, OH, methoxy, ethoxy, —O—CH₂—COOH, —O—CH₂—CO—O-methyl, or —O—CH₂—COOethyl.
 30. The method according to claim 1, wherein: R¹ is hydrogen or methyl; R² is hydrogen or methyl; and R³ is hydrogen, methyl, OH, methoxy, —O—CH₂—COOH, or —O—CH₂—COOethyl. 